Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2

2531 Methionine aminopeptidase-2 (MetAP2), an intracellular enzyme responsible for the removal of the N-terminal initiator methionine from nascent proteins, has been suggested as a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 was identified by ASMS screening. These micromolar hits, typified by A-193400 (MetAP2 IC 50 = 13 μM) and A-444148 (MetAP2 IC 50 = 1.3 μM) were rapidly improved to nanomolar leads based on insights from protein crystallography. Compounds with good enzyme inhibitory activity and promising oral bioavailability in mice such as A-751277 (MetAP2 IC 50 = 0.010 μM, F = 93%) were obtained; however the compounds displayed extensive binding to HSA and had limited activity in cellular assays (EC 50 = 0.40 μM for HMVEC proliferation, EC 50 = 2.1 μM for HT-1080 proliferation). Modifications based on structural information on the binding of lead compounds to domain 3 of albumin allowed the identification of compounds with significant improvements in both parameters such as A-832234 (MetAP2 IC 50 = 0.011 μM, HMVEC EC 50 = 0.007 μM, HT-1080 EC 50 = 0.006 μM) and A-847519 (MetAP2 IC 50 = 0.017 μM, HT-1080 EC 50 = 0.036 μM) which show good cellular activity in both proliferation and methionine processing assays.